A Trial to Find the Safe Dose for BI 891065 Alone and in Combination With BI 754091 in Patients With Incurable Tumours or Tumours That Have Spread

NCT03166631 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: 1379-00012017-000465-74
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 3

Brief Summary

The main objective of the dose-escalation parts of the trial is to determine the maximum tolerated dose (MTD), based on the frequency of patients experiencing dose-limiting toxicities (DLTs), and/or the recommended dose for further development of BI 891065 monotherapy as well as of BI 891065 in combination with BI 754091, and to evaluate its safety and tolerability by monitoring the occurrence and severity of adverse events (AEs). Secondary objectives are the determination of the pharmacokinetic (PK) profile of BI 891065 monotherapy as well as of BI 891065 in combination with BI 754091, and the preliminary assessment of anti-tumour activity.

Conditions

Neoplasms; Neoplasm Metastasis; Carcinoma, Non-Small-Cell Lung

Outcome Measures

Primary Outcomes (4)

• Part A - Maximum Tolerated Dose (MTD) of BI 891065

  Maximum tolerated dose (MTD) defined as the highest dose with less than 25% risk of the true Dose-limiting toxicity (DLT) rate being above 33% during the MTD evaluation period.

  First treatment cycle (MTD evaluation period), up to 21 days.

• Part A - Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period

  DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1.

  First treatment cycle (MTD evaluation period), up to 21 days.

• Part B: Maximum Tolerated Dose (MTD) of BI 891065 in Combination With Ezabenlimab

  Maximum tolerated dose (MTD) of BI 891065 in combination with ezabenlimab, defined as the highest dose with less than 25% risk of the true Dose-limiting toxicity (DLT) rate being above 33% during the MTD evaluation period.

  First treatment cycle (MTD evaluation period), up to 21 days.

• Part B: Number of Patients With Dose-limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period

  DLT is defined as: Hematologic toxicities for patients with solid tumors: Any Grade 5 toxicity; Neutropenia ≥Grade 4 lasting for \>5 days; Febrile neutropenia of any duration; Neutropenia Grade 3 with documented infection; Grade thrombocytopenia 4, or Grade 3 with bleeding or require platelet transfusion; Grade 4 anemia unexplained by underlying disease. Non-hematological toxicities: AST or ALT \>3xULN and concurrent total bilirubin \>2xULN without initial findings of cholestasis; ≥Grade 4 AST or ALT; Any ≥Grade 3 non-hematologic toxicity with some exceptions listed in protocol; Any Grade 2 pneumonitis; Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment; Any treatment-related ≥Grade 2 toxicity that persists and results in an inability to administer BI 754091 on Cycle 2 Day 1.

  First treatment cycle (MTD evaluation period), up to 21 days.

Secondary Outcomes (12)

• Part A: Number of Patients With Dose-limiting Toxicities (DLT) During the Entire On-treatment Period

  From first drug administration until last drug administration plus residual effect period of 30 days, up to 282 days.

• Part A: Number of Patients With Objective Response (OR)

  Up to 252 days.

• Part A: Maximum Measured Plasma Concentration of BI 891065 at Steady State (Cmax,ss)

  Just before drug intake and 0.5**, 1, 2, 3, 4*, 5, 6, 7, 8, 10**, 12*, 24, 36, 47.917, 167.917, 263.917, 335.917, 336.5**, 337, 338, 339, 340*, 341, 342, 343, 344, 346**, 348*, 359.917 hours after drug administration on day 1.

• Part A: Area Under the Concentration Time Curve of BI 891065 Over a Dosing Interval at Steady State (AUCtau,ss)

  Just before drug intake and 0.5**, 1, 2, 3, 4*, 5, 6, 7, 8, 10**, 12*, 24, 36, 47.917, 167.917, 263.917, 335.917, 336.5**, 337, 338, 339, 340*, 341, 342, 343, 344, 346**, 348*, 359.917 hours after drug administration on day 1.

• Part A: Area Under the Concentration-time Curve of BI 891065 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)

  Just before drug intake and 0.5**, 1, 2, 3, 4*, 5, 6, 7, 8, 10**, 12*, 24, 36, 47.917, 167.917, 263.917, 335.917, 336.5**, 337, 338, 339, 340*, 341, 342, 343, 344, 346**, 348*, 359.917 hours after drug administration on day 1.

Study Arms (11)

Part A: 5 mg BI 891065

EXPERIMENTAL

BI 891065 alone

Drug: BI 891065

Part A: 15 mg BI 891065

EXPERIMENTAL

BI 891065 alone

Drug: BI 891065

Part A: 25 mg BI 891065

EXPERIMENTAL

BI 891065 alone

Drug: BI 891065

Part A: 50 mg BI 891065

EXPERIMENTAL

BI 891065 alone

Drug: BI 891065

Part A: 100 mg BI 891065

EXPERIMENTAL

BI 891065 alone

Drug: BI 891065

Part A: 200 mg BI 891065

EXPERIMENTAL

BI 891065 alone

Drug: BI 891065

Part A: 400 mg BI 981065

EXPERIMENTAL

BI 891065 alone

Drug: BI 891065

Part B: 50 mg BI 891065 QD + 240 mg BI 754091

EXPERIMENTAL

BI 891065 in combination with BI 754091

Drug: BI 891065; Drug: BI 754091

Part B: 200 mg BI 891065 QD + 240 mg BI 754091

EXPERIMENTAL

BI 891065 in combination with BI 754091

Drug: BI 891065; Drug: BI 754091

Part B: 400 mg BI 891065 QD + 240 mg BI 754091

EXPERIMENTAL

BI 891065 in combination with BI 754091

Drug: BI 754091

Part B: 200 mg BI 981065 BID + 240 mg BI 754091

EXPERIMENTAL

BI 891065 in combination with BI 754091

Drug: BI 891065; Drug: BI 754091

Interventions

BI 891065 DRUG

Part A, Part B

Part A: 100 mg BI 891065; Part A: 15 mg BI 891065; Part A: 200 mg BI 891065; Part A: 25 mg BI 891065; Part A: 400 mg BI 981065; Part A: 5 mg BI 891065; Part A: 50 mg BI 891065; Part B: 200 mg BI 891065 QD + 240 mg BI 754091; Part B: 200 mg BI 981065 BID + 240 mg BI 754091; Part B: 50 mg BI 891065 QD + 240 mg BI 754091

BI 754091 DRUG

Part B

Part B: 200 mg BI 891065 QD + 240 mg BI 754091; Part B: 200 mg BI 981065 BID + 240 mg BI 754091; Part B: 400 mg BI 891065 QD + 240 mg BI 754091; Part B: 50 mg BI 891065 QD + 240 mg BI 754091

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated, written informed consent form (ICF) in accordance with International Conference of Harmonization-Good Clinical Practice (ICH-GCP) and local legislation prior to any trial-specific procedures, sampling, or analyses
• Patients ≥18 years-of-age at the time of signature of the ICF
• Male or female patients. Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use highly effective methods of birth control (that result in a low failure rate of less than 1% per year when used consistently and correctly)during trial participation and for at least 6 months after the last administration of trial medication. A list of contraception methods meeting these criteria is provided in the patient information.
• Eastern Cooperative Oncology Group (ECOG) score: 0 or 1
• Life expectancy of at least 12 weeks after the start of the treatment according to the Investigator's judgement
• For Parts A and B: Patients with a confirmed diagnosis of advanced, unresectable and/or metastatic solid tumours, who have failed standard treatment, or for whom no therapy of proven efficacy exists, or who are not amenable to standard therapies. Measurable lesions according to RECIST Version 1.1 must be present. Eligibility is limited to the following tumour subtypes in Part B: bladder, colon, breast, Non-small cell lung cancer (NSCLC), ovarian, pancreatic, renal, esophagogastric, sarcoma, prostate, and melanoma.
• For Parts B and C: Patients must have measurable disease per RECIST v1.1, must have at least 1 tumour lesion amenable to biopsy, and must be willing to undergo a biopsy prior to first treatment and another biopsy while on therapy unless clinically contraindicated.
• For Part C: Patients with metastatic NSCLC who developed disease progression (per RECIST v1.1) after the first scan (where SD, Partial Response (PR), or Complete Response (CR) was demonstrated at the first scan), and require new anti-cancer therapy after first line treatment with an anti programmed cell death protein 1 (PD-1)/anti programmed cell death ligand 1 (PD-L1) monoclonal antibody (mAb) (given either as single agent therapy or in combination with a platinum-based chemotherapy regimen).

You may not qualify if:

• Major surgery (major according to the Investigator's and/or Medical Monitor's assessment) performed within 12 weeks prior to randomization or planned within 12 months after screening (e.g., hip replacement)
• Presence of other active invasive cancers other than the one treated in this trial within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin, or in situ carcinoma of uterine cervix, or other local tumours considered cured by local treatment
• Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial
• Previous administration of BI 891065 or BI 754091
• Currently enrolled in another investigational device or drug trial, or less than 30 days since ending another investigational device or drug trial(s), or receiving other investigational treatments.
• Patients who have been treated with any other anticancer drug within 4 weeks or within 5 half-life periods (whichever come earlier) prior to first administration of BI 891065. At least 7 days must have elapsed between the last dose of such agent and the first dose of study drug.
• Persistent toxicity from previous treatments that has not resolved to ≤ Grade 1 (except for alopecia and Grade 2 neuropathy due to prior platinum-based therapy)
• Active, known or suspected autoimmune disease except vitiligo or resolved asthma/atopy
• Interstitial lung disease
• Any of the following cardiac criteria:
• Mean resting corrected QT interval (QTcF) \>470 msec
• Any clinically important abnormalities (as assessed by the investigator) in rhythm, conduction, or morphology of resting Electrocardiograms (ECGs), e.g., complete left bundle branch block, third degree heart block
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication with known or possible risk of QT interval prolongation
• Patients with an ejection fraction (EF) \<55% or the lower limit of normal of the institutional standard will be excluded. Only in cases where the Investigator (or the treating physician or both) suspects cardiac disease with negative effect on the EF, will the EF be measured during screening using an appropriate method according to local standards to confirm eligibility (e.g., echocardiogram \[ECHO\], multi-gated acquisition scan \[MUGA\]). A historic measurement of EF no older than 6 months prior to first administration of study drug can be accepted provided that there is clinical evidence that the EF value has not worsened since this measurement in the opinion of the Investigator or of the treating physician or both.
• Out of range laboratory values are defined as:

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (3)

Florida Cancer Specialists

Sarasota, Florida, 34232, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Froedtert and The Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• Patel MR, Hamilton EP, George B, Kretschmar G, Harada A, Graeser R, Eleftheraki A, Tachibana Y, Yamamoto N. The Second Mitochondria-Derived Activator of Caspases Mimetic BI 891065 in Patients With Advanced Solid Tumors: Results From Two Phase I Studies. Cancer Med. 2025 Dec;14(24):e71451. doi: 10.1002/cam4.71451.

  PMID: 41408891 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Neoplasms; Neoplasm Metastasis; Carcinoma, Non-Small-Cell Lung

Condition Hierarchy (Ancestors)

Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

1-800-243-0127

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2017
• First Posted: May 25, 2017
• Study Start: September 8, 2017
• Primary Completion: September 15, 2020
• Study Completion: October 28, 2020
• Last Updated: November 19, 2024
• Results First Posted: November 19, 2024

Record last verified: 2024-09

Locations

US (3)